Atherosclerosis Calcification: Focus on Lipoproteins

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease.

Keywords: calcium; cardiovascular disease; cholesterol; inflammation; lipids; vascular calcification.

Figure 1

Lp(a) in vascular calcification: mechanisms of actions. Lp(a) is a lipoprotein transporting oxidized phospholipids (OxPL), as well as autotaxin (ATX), a lysophospholipase D that converts lysophosphatidylcholine (LysoPC) from OxPL into lysophosphatidic acid (LysoPA). Lp(a) increases cell mineralization, as well as the expression of pro-calcific proteins, by a mechanism involving the activation of the Notch1 signaling pathway, which, in turn, allows nuclear translocation of the nuclear factor-κB (NF-κB). This results in the induction of IL-6 expression, increasing BMP-2 concentrations, as well as the induction of the expression of RUNX2, osteopontin (OPN) and ALP. LysoPA also increases NF-κB nuclear translocation. These effects are blocked by the presence of E06, a natural monoclonal antibody against OxPL. LPAR: lysophosphatidic acid receptor.

Figure 2

Role of PCSK9 in vascular calcification. PCSK9 expression is high in mouse and human calcified aortic valves, as well as in vitro VICs in the presence of pro-osteogenic medium. PCSK9 increases the number of secreted extracellular vesicles, containing more calcium and ALP, enhances the expression of pro-calcifying markers and lowers those of anti-calcifying mediators. These effects are blocked by evolocumab and alirocumab, two specific antibodies against PCSK9. ALP: alkaline phosphatase.

Figure 3

Illustration of the roles of different (apo)lipoproteins in vascular calcification. VLDL and LDL lipoprotein subfractions, and their oxidized or enzyme-modified forms (OxLDL and ELDL), were shown to stimulate calcium crystal deposition. Components of these particles, such as apoCIII, apoB and cholesterol, were also linked to increased calcification. The same was shown for Lp(a) and the enzyme autotaxin carried by these particles. The hepatic enzyme PCSK9 was shown to stimulate vascular calcification by increasing LDL concentrations through degradation of the LDL receptor. HDL subfractions and the main apolipoprotein found in these particles (apoAI) were shown to reduce calcification, although the oxidized form of HDL (OxHDL) was shown to do the opposite. VIC: valvular interstitial cell; SMC: smooth muscle cell; ECM: extra-cellular matrix.